The major overriding goal of my research career has been to understand how changes in specific genes result in specific diseases. This has required defining the genes involved and derived in greater understanding of the molecular and cellular events underlying these illnesses which have then provided insights to potential new modes of therapy.
Exploration of the pathogenesis of Huntington's Disease
The overall goal of this work is to delineate important steps in the pathogenesis of Huntington's Disease (HD) and to generate knowledge which will lead to novel approaches to treating this disease.
ABCA1—biology and relation to hyperlipidemia and atherosclerosis
Our laboratory identified a gene, called ABCA1, which is absolutely critical for the production of high density lipoprotein (HDL) cholesterol, also known as the “good cholesterol”, which protects against the development of coronary artery disease (CAD). This work will generate important new knowledge about HDL production, risk for CAD and ABCA1 function in specific cell types.
The role of ABCA1 on cellular cholesterol homeostasis and β-cell function
Our findings establish a novel role for the gene ABCA1 in β-cell cholesterol homeostasis and insulin secretion, and suggest that cholesterol accumulation may contribute to β-cell dysfunction in type 2 diabetes, and point to β-cell ABCA1 as a novel therapeutic target for this disease.
Genetic contributions to adverse drug reactions
The debilitating and lethal consequences of adverse drug reactions (ADRs) are one of the leading causes of death in Canada and the US. The goal of the Genotype-Specific Approaches to Therapy in Childhood (GATC) project is to prevent adverse drug reactions (ADRs) by identifying predictive genomic markers of adverse drug reactions, and incorporating these markers into a diagnostic tool that will be implemented to predict and prevent ADRs in children.
Simpson JM, Gil-Mohapel J, Pouladi MA, Ghilan M, Xie Y, Hayden MR, Christie BR. Altered adult hippocampal neurogenesis in the YAC128 transgenic mouse model of Huntington disease. Neurobiol. Dis. 41(2):249-60. (2011) PMID 20875859
Bombard Y, Palin J, Friedman JM, Veenstra G, Creighton S, Paulsen JS, Bottorff JL, Hayden MR, . Factors associated with experiences of genetic discrimination among individuals at risk for huntington disease. 156(1):19-27. (2010) PMID 21069869
Sturrock A, Laule C, Decolongon J, Dar Santos R, Coleman AJ, Creighton S, Bechtel N, Reilmann R, Hayden MR, Tabrizi SJ, Mackay AL, Leavitt BR. Magnetic resonance spectroscopy biomarkers in premanifest and early Huntington disease. Neurology 75(19):1702-10. (2010) PMID 21060093
Xie Y, Hayden MR, Xu B. BDNF overexpression in the forebrain rescues Huntington's disease phenotypes in YAC128 mice. J. Neurosci. 30(44):14708-18. (2010) PMID 21048129
Metzler M, Gan L, Mazarei G, Graham RK, Liu L, Bissada N, Lu G, Leavitt BR, Hayden MR. Phosphorylation of huntingtin at Ser421 in YAC128 neurons is associated with protection of YAC128 neurons from NMDA-mediated excitotoxicity and is modulated by PP1 and PP2A. J. Neurosci. 30(43):14318-29. (2010) PMID 20980587
Loo TT, Ross CJ, Sistonen J, Visscher H, Madadi P, Koren G, Hayden MR, Carleton BC. Pharmacogenomics and active surveillance for serious adverse drug reactions in children. Pharmacogenomics 11(9):1269-85. (2010) PMID 20860467
Madadi P, Hildebrandt D, Gong IY, Schwarz UI, Ciszkowski C, Ross CJ, Sistonen J, Carleton BC, Hayden MR, Lauwers AE, Koren G. Fatal hydrocodone overdose in a child: pharmacogenetics and drug interactions. Pediatrics 126(4):e986-9. (2010) PMID 20837591
Madadi P, Joly Y, Avard D, Chitayat DC, Smith MA, Ross CJ, Carleton BC, Hayden MR, Koren G. Communicating pharmacogenetic research results to breastfeeding mothers taking codeine: a pilot study of perceptions and benefits. Clin. Pharmacol. Ther. 88(6):792-5. (2010) PMID 20739920
Huang K, Kang MH, Askew C, Kang R, Sanders SS, Wan J, Davis NG, Hayden MR. Palmitoylation and function of glial glutamate transporter-1 is reduced in the YAC128 mouse model of Huntington disease. Neurobiol. Dis. 40(1):207-15. (2010) PMID 20685337
Kang MH, Singaraja R, Hayden MR. Adenosine-triphosphate-binding cassette transporter-1 trafficking and function. Trends Cardiovasc. Med. 20(2):41-9. (2010) PMID 20656214
Order of British Columbia – 2009
Canada's Health Researcher of the Year: Canadian Institutes of Health Research Michael Smith Prize in Biomedical and Clinical Research – 2008
Prix Galien (Canada) – 2007